As a method for the preparation of optically active α,α-di-substituted α-amino acid derivatives through optically active 4,4-di-substituted oxazolidine derivatives as a synthetic intermediate, for example, methods described by Dieter Seebach, et al. (refer to non-patent literature 1 and non-patent literature 2) and by Carlos Cativiela, et al. (refer to non-patent literature 3 and non-patent literature 4) have been known.
The method described by Dieter Seebach, et al., however, is an unsuitable method for industrial large-scale synthesis because of the extremely low-temperature reaction conditions needed and, additionally, the yield is low.
On the other hand, the method described by Carlos Cativiela, et al. is a method that includes the processes of diastereoselective alkylation using an optically active cyano ester compound and Sharpless asymmetric oxidation, but in the former process, the low yield, low stereoselectivity and numerous reaction steps are a disadvantage, and in the latter process, the use of a peroxidized compound and numerous reaction steps are a disadvantage, and these procedures are also unsuitable for industrial large-scale synthesis.
Furthermore, optically active 4,4-di-substituted oxazolidine derivatives have been used as a synthetic intermediate for the preparation of glutamate receptor antagonists, which are optically active α,α-di-substituted α-amino acid derivatives, and its usefulness have already been known. Glutamate receptor antagonists have been reported as effective against epilepsy, brain defects following heart bypass surgery and/or transplantation, attack, cerebral ischemia, pain, spinal cord injury, head trauma, hypoxia at birth, cardiac arrest and hypoglycemia-induced damage, anxiety, neurodegenerative diseases, Huntington's chorea, AIDS-induced dementia, eye damage, retinopathy, cognitive deficiency, Parkinson's disease, Alzheimer's disease, multiple sclerosis, or the like (refer to non-patent literature 5 to 7 and patent literature 1).
Additionally, several reports demonstrate that optically active α,α-di-substituted α-amino alcohol derivatives exert an immunosuppressive activity based on a novel mechanism of action (refer to non-patent literatures 8 to 10 and patent literature 2), and the optically active 4,4-di-substituted oxazolidine derivatives of the present invention are considered to be useful synthetic intermediates for the preparation of the optically active α,α-di-substituted α-amino alcohol derivatives.
As the manufacturing method of the substituted methylenephosphonium salt disclosed in the patent literature 2, for example, the following procedure (non-patent literature 11) has been disclosed, and compound (IV′-a) is synthesized from the known compound (IV″-a) through the compound (V-a) as the synthetic intermediate, as shown in the following reaction scheme.

However, this procedure has several disadvantages described below:    (1) In Step 1, methyl iodide, which is a mutagen is used and harmful effects on operators and operational environment are a concern.    (2) In Step 2, the heating condition is indispensable for the reaction to proceed, but the compound (V-a) is thermally unstable and, additionally, partially decomposed before initiation of the reaction and, consequently, low production yield and low purity of the compound (IV′-a) thus obtained are disadvantageous.    (3) As Step 2 is an equilibrium reaction, it is necessary to remove out of the reaction system trimethylamine generated by the progress of the reaction for the reaction to proceed smoothly. Trimethylamine, however, is a malodorous material, and the necessity of special measures such as an amine trap is disadvantageous.    (4) Additionally, in Step 2, long-period heating is needed, and an expensive manufacturing cost, when this method is applied to the industrial manufacturing, becomes a problem.    [Non-patent literature 1] Tetrahedron Letters, vol. 25, 2545 (1984)    [Non-patent literature 2] Helvetica Chimica Acta, vol. 70, 1194 (1987)    [Non-patent literature 3] Tetrahedron, vol. 54, 14963 (1998)    [Non-patent literature 4] Journal of Organic Chemistry, vol. 64, 8220 (1999)    [Non-patent literature 5] Bioorganic Medicinal Chemistry Letters, vol. 8, 447 (1998)    [Non-patent literature 6] Bioorganic Medicinal Chemistry Letters, vol. 8, 925 (1998)    [Non-patent literature 7] Journal of Medicinal Chemistry, vol. 41, 1641 (1998)    [Non-patent literature 8] Journal of Medicinal Chemistry, vol. 43, 2946 (2000)    [Non-patent literature 9] Tetrahedron Letters, vol. 43, 8095 (2002)    [Non-patent literature 10] Synthesis, 1667 (2003)    [Non-patent literature 11] The Journal of Organic Chemistry, vol. 52, 19 (1987)    [Patent literature 1] U.S. Pat. No. 5,578,593 Specification    [Patent literature 2] Japanese Patent Publication (Kokai) Number 2003-4599